Physiological function of hydrogen sulfide and beyond

Abstract

The relatively high concentrations of endogenous sulfide in the mammalian brain were measured in 1989, suggesting that hydrogen sulfide (H2S) might have a physiological function. In 1996 we demonstrated that cystathionine β-synthase (CBS) is a H2S producing enzyme in the brain and that H2S facilitates the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory, by enhancing the activity of N-methyl d -aspartate (NMDA) receptors. The following year we demonstrated that another H2S producing enzyme, cystathionine γ-lyase (CSE) is found in tissues including vasculature and that H2S relaxes them. Based on these observations we proposed that H2S is a neuromodulator and a smooth muscle relaxant. In addition to the function as a signaling molecule, we and others found a cytoprotective effect of this molecule; H2S protects neurons from oxidative stress. This finding led to the identification of the protection of various organs including the heart, pancreas, retina, and the kidney against ischemia–reperfusion injury. From our finding that the brains of CBS knockout mice was still able to produce H2S, we found another pathway; 3-mercaptopyruvate sulfur transferase (3MST) along with cysteine aminotransferase (CAT). 3MST produces H2S in the presence of thioredoxin or dihydrolipoic acid (DHLA). We recently found a novel pathway to produce H2S from d -cysteine, a negative control. d -Amino acid oxidase (DAO) metabolizes d -cysteine to an achiral α–keto acid, 3-mercaptopyruvate (3MP), which is further metabolized to H2S by 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H2S from d -cysteine is 80 times more efficient than that from l -cysteine in the kidney, and the administration of d -cysteine to mice ameliorates renal ischemia–reperfusion injury more effectively than l -cysteine. These results show a therapeutic potential of d -cysteine to the renal diseases and even to the kidney transplantation. Our additional contribution to this field is the discovery of H2S-derived polysulfides, which exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H2S. TRPA1 channels mediate the sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, but its endogenous ligand has not been identified. The sulfane sulfur of polysulfides is reactive electrophile and readily transferred to a nucleophilic protein thiolate, to generate the protein persulfide (sulfhydration). The sulfhydration activity of polysulfides is much greater than H2S. The production of H2S and the physiological function of H2S and polysulfides will be discussed.